PROJECT SUMMARY: Olfactory deficit is a defining symptom of chronic rhinosinusitis (CRS) by current consensus guidelines, but olfactory dysfunction is typically under-reported by patients and under-appreciated by treating clinicians. Previous research has found olfactory deficit in 68% of patients with CRS and 20% with complete anosmia, affecting over 25 million individuals in the United States (US). The ability to predict which patients will have olfactory improvement after treatment of CRS is critical to clinical treatment decision-making. Recent studies suggest that localized inflammation of the olfactory cleft could be associated with to olfactory deficits in CRS, resulting in the presence of sinonasal edema, airflow restriction, and alterations in mucus translocation and olfactory receptor neuron activation. Untreated inflammation may even promote metaplasia, wherein specialized olfactory epithelium is replaced by respiratory epithelium incapable of olfaction. There are no current robust methods to categorize olfactory dysfunction in CRS. This lack of categorization is problematic clinically because, at present, all patients are essentially grouped together despite variations in disease characteristics and treatment outcomes. The result is an inability to provide personalized treatment recommendations and disease prognostication from an olfactory standpoint. Categorization enhances mechanistic insight for clinical studies aimed at evaluating treatments for olfactory dysfunction and increases the likelihood that ideal patients are enrolled in clinical trials based their precise disease characteristics, a particularly important concept as medicine shifts toward targeted therapies and personalized medicine. The studies proposed herein are all hypothesis-testing or hypothesis-generating in nature. Specific Aim 1 utilizes unsupervised cluster analysis to identify olfactory-specific patient clusters based on an extensive array of clinical and biologic characteristics. Specific Aim 2 will incorporate multivariate linear modeling and cluster analysis to assess improvement in olfactory function to identify determinants of olfactory function following either medical or surgical intervention for CRS and predict which patient groups will experience improvement and to what degree. Specific Aim 3 will further incorporate proteomic and cytokine analysis to explore molecular characteristics of identified olfactory-specific patient cluster groups to provide further insight into disease mechanisms and pathophysiology. These aims will be completed by initiating an unprecedented multi-center, prospective, observational cohort study to enroll approximately 1,000 subjects undergoing treatment for CRS and olfactory deficit in US between 2016 and 2021. All study participants meeting inclusion criteria will be evaluated using objective olfactory testing and olfactory-specific quality of life instruments, as well as for indicators of inflammation severity within the olfactory cleft. Olfactory cleft biomarkers will be conducted through sampling / collection of olfactory cleft mucus using polyurethane sponges. Mucus samples will be evaluated using cytokine and proteomic profiling as described in the proposal.